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Pharmaceutical & medical device regulatory update, vol. II, issue 3

Dr. Margaret Hamburg has announced she will resign from her post as FDA Commissioner in March 2015, citing her long service to the Agency and the heavy demands it entailed. FDA's chief scientist Dr. Stephen Ostroff will serve as the Agency's head until President Obama nominates a new commissioner.

In January 2015, the House Energy and Commerce Committee released a discussion draft of the 21st Century Cures Act, a bipartisan bill aimed at overhauling how FDA regulates drugs and devices, which builds on an effort known as the 21st Century Cures Initiative. The initiative launched in April 2014 and has been the subject of many congressional hearings and roundtables, as well as several white papers.

Corresponding to the release of the 21st Century Cures discussion draft, two top Republicans from the Senate Health, Education, Labor and Pensions ("HELP") Committee released "Innovation for Healthier Americans," a report aimed at "identifying and advancing specific steps to better align public policy to support medical innovation and patient access to new medicines and technologies," focusing primarily on ways to improve FDA and the National Institutes of Health ("NIH"). The report, which calls for stakeholder feedback by February 23, 2015, was a precursor to a February 3, 2015 announcement from Senators Lamar Alexander (R-TN) and Patty Murray (D-WA), the Chairman and Ranking Member of the Senate HELP Committee, that they are launching a bipartisan initiative to examine the process for providing safe treatments, devices, and cures to patients and the roles of the FDA and NIH in that process. Similar to the work done on the 21st Century Cures Initiative, the senators are creating a bipartisan working group and plan to hold a series of hearings. Any resulting legislation will likely complement the House's intended 21st Century Cures Act.

The lengthy and long-anticipated 21st Century Cures Act discussion draft addresses regulation of drugs and biologics with an eye toward speeding up approvals (Title I); enhancing discovery and development of new treatments (Title II); changes to the clinical trial process (Title III); reforms for NIH and FDA related to research, hiring, and succession planning (Title IV); and revamping certain aspects of medical device regulation (Title V). A summary of each title is provided below.

Title I. Title I would require FDA to include patient experience data when assessing the risks and benefits of certain therapies and to issue guidance describing the use of surrogate endpoints in the drug-approval process. In addition, it would permit FDA to give early approval to breakthrough therapies and provide a new pathway for approving antibiotics based on the limited and specific patient populations who need them. Another provision of this title seeks to ease patient access to drugs outside of approved clinical trials, commonly referred to as "compassionate use." In order to accelerate new cures for high-need populations, the bill would provide funds to repurpose already-approved drugs for new indications and "streamline" data review for such applications. Title I would also expand exclusivity for several categories of drugs, including new antibiotics, orphan drugs, and certain new drug products if they have an added patient or public health benefit over a previously approved version of the same drug. Perhaps most controversial, one discussion draft proposal would provide up to 15 years of marketing exclusivity for drugs that petition for and receive designation from the Department of Health and Human Services ("HHS") as a "dormant therapy."

Title II. Title II of the draft bill would create an "Innovative Cures Consortium," broader than, but based on, the EU's Innovative Medicines Initiative, to pool the resources of industry, government, and academia to accelerate cure development and delivery by nongovernment entities. Under this title, FDA would be required to issue guidance on accelerating certain therapies, including regenerative medicine and genetic technologies for rare diseases. Title II also proposes definitions for "health software" and related terms that would be incorporated into the Federal Food, Drug, and Cosmetic Act ("FDCA"), which does not currently define these terms. The discussion draft also contains a notation indicating that the drafters are struggling with how to ensure that the definition does not inadvertently exempt products that should be regulated. Data sharing is another key aspect of the draft bill. Title II would require increased data sharing from entities receiving federal funding (through federally funded health insurance programs or NIH grants, for example) and would establish a data-sharing framework to enhance patient treatment and care. The proposed draft legislation would also call for FDA to issue guidance on the coordination of regulatory activities for combination products. The discussion draft contains placeholders for subtitles that would address regulation of diagnostic devices and health care data interoperability, but no further details are available yet.

Title III. Title III focuses on clinical trials and the challenges of balancing the protection of human subjects and resource efficiency for those conducting the trials. One way the bill addresses these challenges is by encouraging the use of adaptive clinical trials, which use prospectively designed benchmarks as decision points to make study design changes. The draft bill would require HHS to provide assistance to any federal agency trying to improve oversight of human subject research, particularly with regard to vulnerable populations. Provisions in this title would also provide a mechanism for FDA to periodically evaluate post-approval studies, taking into account any recent changes in medical practice. Finally, Title III would establish a global pediatric clinical trial network to engage with foreign regulatory entities and share knowledge on pediatric research.

Title IV. Title IV puts a greater focus on the various agencies involved in the discovery, development, and delivery of therapeutic products. Title IV contains proposals to increase research funding for and decrease the administrative burdens on NIH. The discussion draft seeks to accelerate vaccine approval by proposing a 180-day standard timeline and an expedited review process for the Centers for Disease Control and Prevention ("CDC") to evaluate vaccines. Title IV also contains significant proposals related to FDA. It would create a process for FDA to designate eligible infectious diseases for priority review vouchers at least every five years and calls on FDA to issue final guidance on changes to approved biologics. The discussion draft also includes a succession-planning provision addressing how FDA should handle retirements of critical personnel and would promote professional development throughout FDA. The discussion draft also proposes revisions to the Sunshine Act, namely, exempting certain industry-sponsored educational activities from reporting requirements. A provision addressing telemedicine would improve the delivery of health care to Medicare beneficiaries. Title IV contains several other provisions relating to Medicare, which is not the focus of this publication. Finally, this title proposes to ease restrictions on experimental medical devices, subject to listing and informed consent requirements, among others.

Title V. Title V concentrates primarily on medical devices but also contains provisions related to drugs. Certain drugs and biosimilars designated as "American-Manufactured" would be granted an exclusivity extension of undetermined length. Title V would also require FDA to update its Good Manufacturing Practices guidance for drug products. Concerning medical devices, the discussion draft would extend FDA's use of third-party device reviews to two new areas: facility inspections and the assessment and certification of "a facility's capability to evaluate and implement" modifications to approved or cleared devices. Title V also creates premarket notification requirements for Class I devices, relaxes requirements for predicate device indications and humanitarian device exemptions, proposes changes to the classification review process, and sets out supply chain security measures for medical devices similar to those enacted for drugs in 2013. Finally, the draft bill would define "valid scientific evidence" in the medical device context, would require FDA to decide whether to recognize medical device standards developed by outside organizations within 60 days of publication, and would direct FDA to train medical device regulators to use the "least burdensome approach," including publishing updated guidance on the subject.

Although the discussion draft from the 21st Century Cures Initiative is not a formal legislative proposal, the 350-page document has the appearance of a bill in most respects, save a few placeholders and notes. Going forward, the committee will collect comments on the draft and will likely take up the legislation later this year.

White House Releases More Details on President's Precision Medicine Initiative

President Obama has revealed more details about the Precision Medicine Initiative, an interagency project aimed at revolutionizing the way health care professionals treat certain diseases. The initiative, first announced in the State of the Union address, aims to harness recent medical discoveries and accelerate the transition from conventional "one-size-fits-all" medical treatments to personalized medicine, tailored to individual patient needs. The cornerstone of the initiative is a volunteer cohort of at least one million Americans who will provide researchers with data needed to make personalized treatments possible. The President's 2016 budget proposes funding the initiative with an investment of $215 million, $130 million of which will support the development of the volunteer cohort and address privacy concerns about collecting and sharing sensitive health data on such a large scale. The rest of the investment will go toward identifying genomic drivers in cancer for more effective cancer treatments ($70 million), modernizing FDA's regulatory infrastructure ($10 million), and developing an IT framework for secure exchange of health data ($5 million). Whether Congress will fund the President's Precision Medicine Initiative and his other health care proposals will depend on the coming budget negotiations.

President's Proposed FY 2016 Budget Includes $4.9 Billion for FDA

President Obama's 2016 fiscal year budget proposal seeks $4.9 billion for FDA—a nine percent increase over FDA's FY 2015 funding levels—to be used for continued implementation of food safety legislation, to improve medical product quality and safety, and to further fund needed staffing increases and overhead. An FDA fact sheet highlights how funds would be allocated within FDA by product category. In its Justification of Estimates, FDA reports that the proposed budget is structured around FDA's strategic plan framework and would be divided among four major activities: food safety, medical product safety, medical countermeasures, and "other activities" that would include consolidating FDA's facilities, tobacco control, and color certification.

The President's Precision Medicine Initiative calls for the increased use of diagnostic tools, such as genomic sequencing, to tailor treatments to specific patients. In December 2014, FDA released a discussion paper describing the challenges posed by the large amount of data produced by next-generation sequencing and the shortcomings of FDA's traditional regulatory model intended for single-disease detection. FDA will host a workshop on February 20, 2015, to receive public comments as it considers how to regulate these complex tools.

FDA Revises Draft Guidance on Drug Promotional Materials

FDA recently released updated draft guidance on how to explain risks to consumers in advertisements and labeling for prescription drugs, particularly the "consumer brief summary." In the draft guidance, FDA noted concern that consumers are overwhelmed by how risks are currently presented and encouraged the use of "fact boxes" written in "consumer friendly language" instead of long lists of potential side effects. FDA also called for sponsors to more directly state who should not use the advertised product, rather than issuing vague warnings or contraindications.

The Mexican Ministry of Health recently completed a regulatory framework for registering biosimilar drugs and biotechnologies used in treating common chronic conditions like diabetes, arthritis, and hypertension. The regulation establishing the guidelines and requirements for approval takes effect this month. Requirements include manufacturing process controls, clinical trial procedures, and reference drug qualifications.

European Court of Justice Rules on Orphan Drug Market Exclusivity

On January 22, 2015, the General Court of the European Court of Justice held that an orphan medicinal product that has the same therapeutic indication as a previously authorized orphan but that has been independently authorized enjoys 10 years of independent market exclusivity. The case was bought by Teva against a decision of the European Medicines Agency to reject the marketing authorization application for the generic version of the previously authorized orphan (imatinib) on the basis that the later and independently authorized orphan (nilotinib) continued to have market exclusivity for the therapeutic indication in question. Teva's action was dismissed.

In the February 6, 2015, Federal Register, FDA issued a proposed rule to implement Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 ("MMA") governing the approval of 505(b)(2) applications and abbreviated new drug applications ("ANDAs"). According to FDA, it has been implementing the MMA directly from the statute for several years and now seeks to amend its regulations to codify current practice and policy. The proposed rule aims to streamline requirements related to submission of certain patent information, including: Paragraph IV certifications, corrections and changes, timing of submissions, amending or supplementing patent certifications, notification of commercial marketing, and notification of court actions or documented agreements. Comments due May 7, 2015.

On January 26, 2015, the European Medicines Agency launched an electronic repository for periodic safety update reports ("PSURs") and their assessment reports. The central platform, created in accordance with the pharmacovigilance legislation of the EU, will contain all information related to PSURs in the EU with the aim of facilitating the assessment of PSURs by medicines regulatory authorities in the EU.

FDA Authorizes Emergency Use of IV Diagnostics for Ebola Detection

In the February 9, 2015, Federal Register, FDA issued three emergency use authorizations, one of which was amended after initial issuance, for three in vitro diagnostic devices for detection of the Ebola virus in response to the 2014 Ebola virus outbreak in West Africa.

FDA Reopens Docket for Comments on GDUFA

In the February 6, 2015, Federal Register, FDA reopened the docket to solicit public comment on certain topics related to implementation of the Generic Drug User Fee Amendments of 2012 ("GDUFA") and the GDUFA Commitment Letter that accompanies the legislation. Comments due March 9, 2015.

FDA-CDER Continues Site Tours Program, Invites Pharma to Participate

In the February 6, 2015, Federal Register, FDA announced it will continue CDER's Regulatory Project Management Site Tours and Regulatory Interaction Program. In this program, small groups of regulatory project managers observe operations of pharmaceutical manufacturing and packaging facilities, laboratories, and regulatory affairs operations. According to FDA, the purpose of the program is not to inspect, assess, judge, or perform a regulatory function but is meant rather to improve mutual understanding and to provide an avenue for open dialogue.Pharmaceutical companies may submit proposed agendas to the Agency by April 7, 2015.

FDA Republishes PMA Order for Automated External Defibrillator

In the February 3, 2015, Federal Register, FDA republished its final orderEffective Date of Requirement for Premarket Approval for Automated External Defibrillator (originally published in the January 29, 2015, Federal Register) to correct an inadvertent omission of a comment regarding adverse tissue reaction as a risk to health and the Agency's response to that comment. The final order requires the filing of premarket approval applications ("PMA") for automated external defibrillator ("AED") systems, which consist of an AED and those AED accessories necessary for the AED to detect and interpret an electrocardiogram and deliver an electrical shock (e.g., pad electrodes, batteries, adapters, and hardware keys for pediatric use). Effective May 4, 2015 (for AEDs and accessories legally marketed by that date).

FDA Modifies Recognized Consensus Standards for Medical Devices

In the January 27, 2015, Federal Register, FDA published modifications it is making to the list of standards FDA recognizes for use in premarket reviews. This publication will assist manufacturers that elect to declare conformity with consensus standards to meet certain requirements for medical devices.

FDA Invites Comments on WHO Recommendations for Narcotics

In the January 27, 2015, Federal Register, FDA solicited comments for preparing the United States's position concerning recommendations by the World Health Organization ("WHO") to impose international manufacturing and distributing restrictions on certain drug substances under international treaties. These recommendations will be discussed during a meeting of the United Nations Commission on Narcotic Drugs in Vienna, Austria, in March 2015. Comments due February 26, 2015.

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